Cefamandole is a generic term used to identify a chemical compound, 7-(D-.alpha.-hydroxyphenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)meth yl-3-cephem-4-carboxylic acid, having the formula ##SPC1##
This compound is active as a broad spectrum antibiotic effective in controlling diseases caused by a wide variety of Gram-positive and Gram-negative microorganisms.
Cefamandole is one of the semi-synthetically produced cephalosporins. It can be prepared, for example, by treating 7-aminocephalosporanic acid, commonly known as 7-ACA, suitably protected in the 7-position, for example, by a formyl group, with 1-methyl-1H-tetrazole-5-thiol, or an alkali metal, alkaline earth metal, or ammonium salt thereof, to produce the corresponding 7-formamido-3-(1-methyl-1H-tetrazol-5-ylthio)-methyl-3-cephem-4-carboxylic acid. This product then can be cleaved in accordance with known techniques to produce the corresponding 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-3-cephem-4-carboxylic acid, and the resulting cleaved product then can be acylated, for example, employing anhydro-O-carboxy-mandelic acid, to produce the desired cefamandole. The aforementioned sequence is typical of several methods which are available in the preparation of cefamandole. For example, the aforementioned acylation step can be carried out employing a mixed anhydride form of D-mandelic acid in which the hydroxyl group has been protected by a suitable blocking group, for example, a formyl or an acetyl group. The mixed anhydride then can be used as acylating agent for the 7-aminocephalosporin compound to form the hydroxy-protected cefamandole which then is cleaved to produce the desired cefamandole product. Alternative methods for effecting acylation of the 7-amino group are well known to those of ordinary skill in the art.
The source of the 7-formamido derivative of 7-ACA employed in the foregoing sequence is 7-ACA itself, and the latter can be obtained from cephalosporin C, more precisely known as 7-(5-aminoadipamido)cephalosporanic acid, which can be prepared by cultivating a cephalosporin C-producing organism in a suitable nutrient medium. The cephalosporin C can then be readily converted to the corresponding nucleus compound, 7-ACA, by cleaving the 5-aminoadipamyl side chain by known procedures.
A highly preferred form of cefamandole is its sodium salt derivative which has the following formula: ##SPC2##
This form of cefamandole, however, does not exist in crystalline form, or at least a crystalline form has not as yet been discovered. As a result of this fact, two deficiencies have been noted. First, cefamandole sodium has been found to be purifiable to the extent necessary for administration only by very difficult and cumbersome techniques. Secondly, amorphous cefamandole sodium does not exhibit the degree of stability that one would desire, and certainly not such as one would expect from a corresponding crystalline structure.
In this context, therefore, it has become desirable to develop a crystalline form of cefamandole sodium, which form would be useful in purifying cefamandole sodium itself. This purification sequence then would comprise preparation of a crystalline derivative of cefamandole sodium from an impure or relatively impure lot of cefamandole sodium. The crystalline derivative then could be isolated from the impure mixture leaving impurities behind. Any such desirable crystalline derivative then would be usable as such or would exhibit properties which would permit its ready decomposition with regeneration of cefamandole sodium itself in purified form.
Such a derivative would permit purification of impure amorphous cefamandole sodium; additionally, it would permit the retention of cefamandole sodium in a highly stable form, which form could be decomposed with regeneration of the cefamandole sodium at some point prior to packaging of the cefamandole sodium in a unit suitable for ultimate administration.
Such a discovery forms the basis of this invention. It is an object, therefore, of this invention to provide a novel composition of matter comprising a stable, crystalline derivative of cefamandole sodium.
It is a further object of this invention to provide a method for purifying cefamandole sodium by preparing and recovering a defined crystalline derivative thereof and subsequently decomposing the derivative to recover cefamandole sodium itself.